Catalytic synthesis of γ-alkoxy-α-keto esters

Article abstract of DOI:10.1055/s-0030-1259560

Copper(II) triflate effectively catalyzes the reaction of (trimethylsilyloxy)acrylic esters and acetals to form -alkoxy - keto esters. The reaction proceeds under mild conditions providing products in good to excellent yields. The substrate scope was investigated, and it was demonstrated that the products could be converted into related compounds such as γ-hydroxy -α- keto esters and α-oximes. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259560

LETTER
671
Catalytic Synthesis of g-Alkoxy-a-keto Esters
g
-Alkoxy-
a
-
keto
E
n
st e
r
ke Krebs, Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 18 January 2011
zene (1a) and ethyl 2-(trimethylsilyloxy)acrylic ester (2a)
was chosen as model system. In an initial attempt, 10
mol% of Sc(OTf)3 was employed. After 30 minutes the
desired a-keto ester 3a was obtained in 77% yield
Abstract: Copper(II) triflate effectively catalyzes the reaction of
(trimethylsilyloxy)acrylic esters and acetals to form g-alkoxy-a-
keto esters. The reaction proceeds under mild conditions providing
products in good to excellent yields. The substrate scope was inves-
tigated, and it was demonstrated that the products could be convert- (Table 1, entry 1). Several other metal triflates such as
Fe(OTf)2 and Cu(OTf)2 also catalyzed the reaction.13 Met-
al chlorides such as YCl3 and FeCl2 were inactive (entries
ed into related compounds such as g-hydroxy-a-keto esters and
a-oximes.
Key words: copper(II)triflate, acetals, (trimethylsilyloxy)acrylic
ester, g-alkoxy-a-keto ester, a-oximes, g-hydroxy-a-keto ester,
Mukaiyama–aldol
3 and 4). In contrast to Cu(OTf)2, which furnished the keto
ester in very high yield, CuCl2 rendered the desired prod-
uct only in trace amounts (entry 5). Use of Cu(OTf)2 al-
lowed to reduce the catalyst loading to 1 mol%, and under
those conditions the keto ester was obtained in 85% yield
(entry 8). Triflic acid proved to be too acidic, and even the
use of 1 mol% led to an immediate decomposition of the
reactants (entry 9).
(Trialkylsilyloxy)acrylic esters are interesting compounds
containing both an electron-donating trialkylsilyloxy and
an electron-withdrawing alkoxycarbonyl group at C1 of
an olefinic core. Although they are easily accessible from
the corresponding pyruvates and trimethylsilyl chloride,1
only a few applications can be found in the literature.
Those include the use of (trimethylsilyloxy)acrylic esters
in the syntheses of hetusolonic and ulosonic esters2 as
well as tetrahydrocyclobuta[c]quinilon-3(4H)-ones.3 Fur-
thermore, radical reactions have been reported.4 Most sig-
nificant is their role as precursors for syn-b-amino-a-
hydroxy acids5 and b,g-unsaturated a-keto esters.6–9 Sug-
imura was the first to report a synthetic protocol for the
formation of g-alkoxy-a-keto esters,10 which was then
extended to the preparation of a-oxo-b,g-unsaturated
esters.11 In the original report ethyl 2-(trimethylsilyl-
oxy)acrylic ester (2a) was reacted with an acetal in the
presence of a Lewis acid. In order to achieve reasonable
results an excess of BF3·OEt2 in combination with temper-
atures below –30 °C was required. Apparently, the suc-
cess of the reaction was limited by the acid sensitivity of
both starting materials. The acrylic ester decomposed in
the acidic medium, and the acetal quickly retransformed
to the corresponding aldehyde. To the best of our knowl-
edge, there has been no report on a catalytic version of this
reaction. Considering its synthetic potential we decided to
search for a Lewis acid that was sufficiently strong to cat-
alytically promote this interesting C–C bond formation
being at the same time mild enough to avoid the decom-
position of the starting materials.
Table 1 Effects of Various Lewis Acids on the Reaction between
Acetal 1a with Acrylic Ester 2a
OMe
OMe O
OSiMe3
OEt
Lewis
acid
OEt
OMe
+
O
O
1a
2a
3a
Entry
Lewis acid (mol%)
Sc(OTf)3 (10)
Fe(OTf)2 (10)
YCl3 (10)
Yield (%)a
77
1
2
3
4
5
6
7
8
9
73
traces
traces
traces
99
FeCl2 (10)
CuCl2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (1)
TfOH (1)
79
85
–
a Yields after column chromatography.
In order to further optimize the reaction conditions, the in-
fluence of the solvent was investigated. Whereas no con-
version or poor results were observed in reactions
performed in diethyl ether or THF, dichloromethane
proved to be the solvent of choice. Initially, the reactions
were started at –78 °C and allowed to warm to 0 °C. Tem-
perature studies revealed, however, that no deep cooling
was required and that the reaction was best carried out in
Because scandium triflate [Sc(OTf)3] catalyzed a wide va-
riety of organic reactions,12 it became a prime candidate in
our search. The reaction between (dimethoxymethyl)ben-
SYNLETT 2011, No. 5, pp 0671–0673
x
x.
x
x.
2
0
1
1
Advanced online publication: 22.02.2011
DOI: 10.1055/s-0030-1259560; Art ID: B01911ST
© Georg Thieme Verlag Stuttgart · New York

672
A. Krebs, C. Bolm
LETTER
an ice bath (ca. 4 °C). Monitoring by TLC showed that the substituents reacted remarkably well, and despite the ster-
starting materials were completely consumed within 20– ic hindrance at the reaction site of the respective starting
30 minutes when 10 mol% of Cu(OTf)2 was employed as materials the yields were good (entries 10–13). Thus, halo
catalyst. Under those conditions, no significant side reac- keto esters 3j and 3k were obtained in 69% and 63% yield,
tions occurred, and even without the common aqueous respectively (entries 10 and 11). Acetal 1l having a bulky
workup the analytically pure keto ester was isolated in ortho nitro group gave the corresponding product (3l) in
nearly quantitative yield by simple column chromatogra- only 30% yield. Changing the catalyst to Sc(OTf)3 in-
phy (Table 1, entry 6).
creased the yield to 84% (entry 12). Also 1m, prepared
from 2-naphthaldehyde, reacted well, affording keto ester
3m in 88% yield (entry 13). Reactions involving 1n de-
rived from 3-phenyl propanal and aliphatic acetal 1o
proved challenging, and the yields of the corresponding
keto esters 3n and 3o were only 35% and 46%, respective-
ly (entries 14 and 15).
Next, the impact of a structural alternation of the acrylic
ester silyl group was evaluated (Figure 1). Although com-
pounds 2b and 2c bearing a dimethylphenyl silyl and a
methyldiphenyl silyl group, respectively, proved to be
more stable and suitable for purification by column chro-
matography, their use in the catalytic synthesis of a-keto
ester 3a remained inefficient. Compared to the reaction
with 2a the yields of that product were low (35% with 2b,
and 47% with 2c).
Table 2 Substrate Scopea
OR2
O
OR2
OR2
OSiMe3
OEt
Cu(OTf)2
(10 mol%)
OEt
+
R1
R1
OSiR2R'
O
2a
O
1a–o
Entry
1
3a–o
OEt
2a R = R' = Me
2b R = Me, R' = Ph
2c R = Ph, R' = Me
Product
3a
R1
Ph
Ph
Ph
Ph
Ph
R2
Yield (%)b
O
Figure 1 Ethyl (triorganylsilyloxy)acrylic esters applied in the re-
action with 1a to yield a-keto ester 3a
Me
Et
99
65
83
69
76
94
51
25
73
69
63
84
88
35
46
2
3b
3c
Table 2 summarizes the substrate scope for catalyses per-
formed under the optimal reaction conditions.14 Except
for (dibenzylmethyl)benzene (1d), which had to be pre-
pared from benzaldehyde and trimethylsilyl-protected
benzyl alcohol by FeCl3 catalysis,15 acetals 1 could easily
be accessed in large quantities from the corresponding al-
dehydes and alcohols in the presence of hydrochloric acid.
As mentioned before, (dimethoxymethyl)benzene (1a) re-
acted smoothly with ethyl 2-(trimethylsilyloxy)acrylic es-
ter (2a) to give the desired g-alkoxy-a-keto ester 3a in
almost quantitative yield (entry 1). The impact of the ace-
tal moiety was determined by the following experiments.
With (diethoxymethyl)benzene (1b), the corresponding
keto ester 2b was obtained in only 65% yield (entry 2). Di-
isopropyl acetal 2c proved to be more reactive leading to
product 3c in 83% yield (entry 3). With the goal to intro-
duce a cleavable ether group, dibenzyl acetal 1d was ap-
plied. After a reaction time of only 20 minutes the
corresponding keto ester 3d was isolated in 69% yield
(entry 4). Also an allyl ether could be formed, and 3e was
obtained in 76% yield starting from 1e (entry 5).
3
i-Pr
Bn
4
3d
3e
5
allyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6
3f
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-BrC6H4
2-ClC6H4
2-BrC6H4
2-NO2C6H4
naphthyl
7
3g
8
3h
3i
9
10
11
12c
13
14
15
3j
3k
3l
3m
3n
3o
PhCH2CH2
hexyl
a Reaction conditions: acetal 1, Cu(OTf)2 (10 mol%), acrylic ester 2
(1.5 equiv), CH2Cl2, 0 °C.
Next, the influence of the substitution pattern of the aro-
matic ring was examined. To our delight various function-
al groups were tolerated. For example, p-methoxy-
substituted aryl acetal 1f reacted smoothly with 2a to af-
ford keto ester 3f in 94% yield (entry 6). If the arene had
a more electron-withdrawing group such as a nitro or halo
substituent, the yields of the resulting keto esters were
lower, but commonly still good (entries 8–12). Only in the
catalysis with p-nitro-bearing 1h the yield of 3h remained
unsatisfying (25%, entry 8). In none of those cases, nei-
ther extending the reaction time nor raising the tempera-
ture had a positive effect. Substrates with ortho
b After column chromatography.
c Use of 10 mol% of Sc(OTf)3.
Because literature protocols described the removal of the
g-alkoxy substituents rendering synthetically useful b,g-
unsaturated keto esters by elimination,11 we decided to fo-
cus our efforts on transformations retaining the dense
functionalization of the products. The initial attempts tar-
geted on the preparation of g-hydroxy-a-keto ester 5 by
debenzylation of 3d (Scheme 1). To our surprise, utilizing
a standard hydrogenation protocol with Pd/C in methanol
Synlett 2011, No. 5, 671–673 © Thieme Stuttgart · New York

LETTER
g-Alkoxy-a-keto Ester
673
led to overreduction, and instead of 5 hydroxy ester 4 was
formed.16 After several trials it was found that the desired
benzyl cleavage was possible under oxidative conditions
using 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (DDQ)
as reagent. In this manner g-hydroxy keto ester 5 was ob-
tained in 45% yield. With the goal to demonstrate a func-
tional-group conversion of the a-keto moiety, g-methoxy-
a-keto ester 3a was treated with hydroxylamine
(Scheme 1). In this case, a smooth reaction occurred, and
oxime 6 was obtained in 96% yield (Scheme 1). In the
long run, the high efficiency of this process might render
it interesting for the synthesis of substituted unnatural
amino acid derivatives.
References and Notes
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OH
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(14) General Procedure for the Synthesis of the g-Alkoxy-a-
keto Esters
OBn
O
O
OEt
4
5
OH
O
N
O
DDQ
OEt
3d
O
OH
O
OMe
O
OMe
OEt
OEt
H2N-OH
O
6
3a
Scheme 1 Conversions of keto esters 3d and 3a
In summary, we developed a simple catalytic approach to-
wards g-alkoxy-a-keto esters, which proceeds under mild
conditions in reasonable reaction times. No workup is re-
quired, and analytically pure products are obtained by
simple column chromatography of the crude products.
Various functional groups are tolerated, and depending on
the substitution pattern good to excellent yields can be
achieved. Straightforward functional-group conversions
allow to access g-hydroxy-a-keto esters and to address the
a-keto group. Our current studies have the goal to develop
a catalytic asymmetric version of this reaction and to find
further applications of the densely functionalized prod-
ucts in organic synthesis.
Cu(OTf)2 (0.04 mmol) was dissolved in dry CH2Cl2 (2 mL)
and cooled to 0 °C. The acetal (0.4 mmol) and the acrylic
ester (0.6 mmol) were added, and the reaction was monitored
by TLC. After consumption of the starting material, the
crude reaction mixture was directly subjected to column
chromatography to yield the pure products 3a–o.
Ethyl 4-Methoxy-4-phenyl-2-oxobutyrate (3a)17
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.14 Hz, 3 H,
CH3), 2.98 (dd, J = 16.8, 4.4 Hz, 1 H, CH2), 3.20 (s, 3 H,
OCH3), 3.41 (dd, J = 16.8, 9.2 Hz, 1 H, CH2), 4.31 (q,
J = 7.14 Hz, 2 H, CH2), 4.73 (dd, J = 9.2, 4.4 Hz, 1 H, CH),
7.29–7.40 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
d = 13.9 (CH3), 47.5 (CH2), 56.7 (OCH3), 62.4 (CH2), 78.9
(CH), 126.4 (Ar), 128.0 (Ar), 128.5 (Ar), 140.1 (Ar), 160.6
(CO), 191.8 (CO) ppm.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Y.; Nakamura, T.; Sakaguchi, M.; Ochiai, H.; Yoshida, Z.
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Acknowledgment
This study was supported by the Fonds der Chemischen Industrie.
Initial discussions with Dr. A. Torrens (Esteve) were stimulating for
the project.
(17) Watanabe, M.; Kobayashi, H.; Yoneda, Y. Chem. Lett. 1995,
163.
Synlett 2011, No. 5, 671–673 © Thieme Stuttgart · New York

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